Elevation of body temperature to between 4l.8 and 42.4 C is now being used both alone and together with chemotherapeutic agents to treat patients with cancer. The mechanisms by which hyperthermia is cytotoxic are poorly understood as are the ways in which elevated temperature affects cell killing by chemotherapeutic agents. We propose to study the interaction between hyperthermia and selected chemotherapeutic drugs utilizing both in vitro and vivo systems. Our general approach will be to test for synergistic cytotoxicity by measuring in vitro colony survival in Chinese hamster ovary cells and by measuring the in vitro colony survival of RT9 astrocytoma cells after in vivo treatments. We then plan to study the mechanism behind the observed increased cytotoxicity by examining such things as altered drug uptake and enzyme inactivation. We will also study the scheduling of the drugs with heat in order to maximize cell kill. These studies should suggest clinically useful combinations of drugs with heat as well as provide basic cellular pharmacologic data. This work is already underway and we have discovered an interesting relationship between methotrexate and adriamycin cytotoxicity when each is combined with heat. In addition we have found that the rate of heating to peak treatment temperature is a critical determinant of the cell kill achieved. Our ultimate aim is to use these studies as starting points in the selection of drugs and hyperthermia schedules for clinical use.